| Title of Invention | METHODS AND APPARATUS FOR MAKING PARTICLES USING SPRAY DRYER AND IN-LINE JET MILL |
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| Abstract | metheds and appuratur are privided for making particles comparsing (1) spraying an emulstion solution or sos- pension, which comprise a solvent and a bult inulcnal (e.g., a phannaceuiletal agent). thought all atulpizer(14) and into a primary Urving chamber (12) having a drying gas following therthrough, to from droplets comprising the solvent and bulk matchal dispersed in the drying gas (b) eraporning, in the primary draying chamber (12), an loast a portion of the solvem into the drying gas to solidify the droplets and rorm paricles dispersed in draying gas and flowing the partiles and of least a portion or the drying gas though a jet mill (24) to deageglomerate or grind the parthcles. By coupling spray drying with "in-line" jet milling, a single step process is ereaied from two separate unit openations. and an additional colletion step is advanlagcosty climtred. The one-step, in-line process has further advanges in utsc and cost of proccessing. |
| Full Text | METHODS AND APPARATUS FOR MAKING PARTICLES USING SPRAY ORYER AND IN-LINE JET MILL Background of the Invention 5 This invention is generally in the field of process equipment and methods for making particles, and more particularly to meihods of deagglomerating or grinding spray dried particles. Spray drying is commonly used in the production of particles for many applications, including Pharmaceuticals, food, cosmetics, fertilizers, dyes, and 10 abrasives. Spray drying can be tailored to create a wide spectrum of particle sizes, including microparticles. Spray dried particles are useful is in variety of biomedical and pharmaceutical apphcation, such as the deliver of therapeutic and diagnostic agents, as described for example in U.S. Patent No. 5,853,698 to Straub et al.; U.S. Patent No. 5,855,913 to Hanes et al.; and U.S, Patent No, 5,622,657 to Takada et al. For these 15 applications: microparticles having very specific sizes and size ranges often are needed in order to effectively deliver the active agents. particles may tend in agglomerate during their production and processing, therehy undesirably astrering the effective size of the particles, to the detriment or the particle formulation's perfomance and/or reproducibility- In other circumstances, the 20 particles made may simply be larger than desired for a particular application Therefore, after they are produced, particles may require additional processing for size reduction and/or deagglomeration. In one common appmach, sepsrate bstch process steps are ussed, For example, particles are made by a known sptay drying process, collected, and then ground in a 25 second, separate step. Such a batch method, however, undesirably requires the use of a tranafer step from the spray dryer to the mill, which, for an aseptic process, mey be difficult to perform. Such a batch process also requires two separate collection steps that are both associated with a yield loss. It would be desirable to provide a sterile particle production and milling process and to mimimize product yield losses, reduce 30 material transfer steps, reduce process time, and reduce production costs, In addition, laboratory scale methods for producing microparticle pharmaceutical formulations may require several steps, which may not be readily or efficiently ttansferred to larger scale production, It would be desirable for the microparticle production and deagglomeration l WO 2004/060547 PCT/US2003/037108 (or grinding) process to be adaptable for efficient, tost effective, commercia scale production. Summray of the Invention 5 Methods and apparatus are provided for meking particles in an in-inline process. comprising: (a) spraying on emusion, solution, or suspension, which comprises a solvent and a bulk material through an atomizer and into a primary drying chamber having a drying gas inlet, a discharge outlet, and a drying gas flowing therethrough, to form droplets comprising the solvent and the hulk material, wherem the dioplete are 10 dispensed in the drying gas; (b) evaporating, in the primary drying chamber, at least a portion of the solvent into the drying gas to solidify the droplets and form particles dispersed in the drying gas, the particles dispersed in the drying gas being a feedstream; and (c) flowing the particles of the feedstream through a jet mill to deagglomerate or grind the particles. This process using spray drying coupled with "in-line" jet miliing 15 eliminates an aseptic transfer from the spray dryer to the jet mill (which would be particularly important for making pharmaceutical formulations comprising the particles) and an additional collection step that would be associated with a yield loss. The inline process can effectively cut processing time by at least one half compared to a two step process. 20 In a preferred embodiment of the method, step (c) is condueted to deagglomaerate at least a portion of agglomerated particles, if any, while subscautjally maintaining the size and morphology of the individual particles. Altermativety, step (c) can be conducted to grind the particles. Preferably, the feedsceam of step (b) is directed dirough a particle coccentration 25 means to separate and remove at least a portitai of the drying gas from the feedstream. In ons embodiment, the particle concentration means comprises a cyclone separator. In one embodiment, the cyclone separates between about 50 and 100 vol.% of the drying gas from the particles. In one embodiment of the method, the feedsteam of step (b) is directed, before 30 step (c), through at least ant secondary drying chamber in fluid commumcarion with the discharge outlet of the primary drying chamber to evpporate a second portion of the solvent into the drying gas. In a preferred embodiment, the secondary drying chamber comprises tubing having an inlet in fluid communication with the discharge outlet of 2 WO 2004/060547 PCT/US2003/037108 the primary drying chamber, wherein the ratio of the cross-sectional area of the primary drying chamber to the cross-sectional area of the tubing is at least 4.3, and whetiein the ratio of the length of the tubing to the length of the primary drying chamber is at least 2:1. 5 In another embodiment of the method, multiple nozzles are used in step (a) to introduce multiple emulsions, solutions, suspensions, or combinations thereof. In one embodiment, the bulk material comprises a pharmaceutical agent. The pharmaceutical agent may be a therapeutic, a prophylactic, or a diagnostic agent. In one embodiment, the therapeutic or prophylactic agent comprises a hydrophobic drug and 10 the particles are microspheres having voids or pores therein, In another embodiment, the bulk material comprises a diagnostic agent, such as an ultrasound contrast agent or another agent for diagnostic imaging. In another embodiment, the bulk material further comprises a shell forming material, such as a polymer (e.g,, a biocompatible synthetic polymer), a tipid, a sugar, a protein, an amino acid, or a combination thereof. 15 In a preferred embodiment, the particles are microparticles, In one embodiment, the microparticles comprise microspheres having voids or pores therem. In one smbodiment, the bulk material comprises a therapeutic or prophylactic agent. In one embodiment, the therapeutic or prophylactic agent comprises a bydrophobic drug and the particles are microspheres having voids of pores threin, In 20 another embodiment, the bulk material comprises a diagnostic agent, such as an ultrasound contrast agent or other agent for diagnostic imaging. In one embodiment, the method further comprises adding an excipient material Or pharmaceutical agent to the feedstream of step (b). For example, this could be done after the feedstream has flowed through a particle concentration means to separate and 25 remove at least a portion of the drying gas from the feedstream, In another example, this could be done before the feedstream has flowed through a particle concentration means to separate and remove at least a portion of the drying gas from the feedstream, In a preferred embodiment, the excipient or pharmaceutical agent is in the form of a dry powder, Examples of the excipient material include amimo acids, proteins, polymers, 30 carbohydrates, starclies, surfactant, and combinations thereof In another aspect, a method is provided for making a dry powder blend. The method includes the steps of (a) spraying an emulsion, solution, or suspension, which comprises a solvent and a bulk material, (trough an atomizer and into a primary drying 3 WO 2004/060547 PCT/US2003/037108 chamber having a trying gas inlet, a discharge outlet, and a drying gas flowing therethrough, to form droplets comprising the solvent and the bulk material, therein the droplets are dispensed in the drying gas; (b) evaporating, in the primary drying chamber, at least a. portion of the solvent into the drying gas to solidify the droplets and 5 form particles dispersed in the diying gas, the particles dispersed in the drying gas being a feedstream; (c) adding a dry powder excipient material to the feedstream to farm a blended feedstream; and (d) flowing the particles and excipient material through a jet mill to deagglomcrate or grind the particles and excipientmaterial. Preferably, the method includes directing the feedstream of step (b) through a particle concentration 10 means to separate and remove at least a portion of the drying gas from the feedstream. In one embodiment, the particles are microparticles comprising a pharmaceutical agent and the excipient material is in the form of microparticles having a size that is larger than the size of the microparticles comprising a pharmaceutical agent. In a preferred embodiment, step (d) is conducted to deaggtomerate at least a portion of agglomerated 15 particles if any, while substantially maintaining the size and morphology of the individual particles. In another embodiment, a second pharmaceutical agent can be added in step (c) in place of or in addition to the exoipient. In another aspect, an apparatus is provided for making particles and deagglomenrating or grinding them. in a prefered embodiment, the apparatus 20 comprises: (a) an atomizer disposed for spraying an emulsion, solution, or suspension which comprises a solvent and a bulk material to form droplets of the solvent and the bulk material; (b) a primary drying chamber having a diyjng gas inlet and a discharge outlet, the stomizer being located, in the primary drying chamber which provides for evaporation of at least a portion of the solvent into the drying gas to solidify the 25 droplets and form particles dispensed in the drying gast and (c) a jet mill having in intel in fluid communication with the discharge outlet paimary drying chamber, the jet mill being operable to reoeive the particles dispersed in at least a portion of the drying gas and grind or deaggiomerate the particles. In one embodiment, the apparatus further includes at least one secoridary drying 30 chamber interposed between, and in fluld communication with, the discharge outlet of the primary drying chamber and the inlet of the jet mill, which provides additional drying of the particles, i,e, provides tor evaporation of a second portion of the solvent into the drying gas, In one version, the seconnaiy drying chamber comprises tubing 4 WO 2004/060547 PCT/US2003/037108 having an inlet in fluid communication with the discharge outlet of the primary drying chamber, wherein the ratio of the cross-sectiooal area of the primary drying chamber to the cross-sectional area of the tubing is at least 4:3, and wherein the ratio of the length of the tubing to the leogth of the primary drying chambet is at least 2:1. 5 in one embodiment, the apparatus also includes a particle concentratian means, such as a cyclone separetor, to separate and remove at least a portion of the drying gas from the particles, wherem the particle concentration means has a particle discharge outler in fluid communication with the inlet of the jet null. In another embodiment, theapparatus further comprises a collection eychloae to 10 separata the drying gas from the deagglomerated or ground particles that are dischaged from the jet mill Optionally, the apparatus includes a control valve to contcol the flow rate of the drying gas discharged from the collection cyclone, a control valve to control the flow rate of the drying gas discharged from the particle concentration means, or both of these control valves. 15 In one embodiment, the apparatus further comprises a means for introducing an excipient material into the particles and drying gas flowing between the discharge outlet of the primary drying chamber and the inlet of the jet null. This apparatus can be used, for example to make a dry powder blend in a single step, i.e., without intemiediate collection and hlending steps between spray drying and jet milling. 20 In one embodiment the apparatus further comprises multiple nozzles to introduce separate emulsions, solutions, suspensions, or combinations thereof into the primary drying chamber. The multiple nozzles of this apparatus can be used, for example, to introduce materials that comprise a pharmaceutical agent, an excipient, ot combinations thereof. The multiple nozzles can be used, for example, to spray the 25 same material in order to increase the throughput or can be used to spray diffetent materials in order to create dry powders that are mixtures of different partieles, In another aspect, phamnacoutical compositions are provided. These compositions comprise particles or dry podert blends mode by the spray drying and in- line jet milling methods described herein. Brief Description of the Drawings FIG. 1 is a process flow diagram of one erabodiment of a process for making mieroparticles by spraying drying with in-line jet milling to deagglomerate or grind the 5 WO 2004/060547 PCT/US2003/037108 micropartieles. FIG. 2 is a process flow diagram of one embodiment of a process for making blends of microparticles by spray drying with in-line exeipient feeding and in-line jet milling. 5 FIG. 3 is a cross-sectional view of a typical jet mill that can be incorpotated into the in-line process for spray drying and jet milling. Detailed Description of the Invention Process systems and methods have been developed for making particles, such as 10 nricroparticles, by sptay drying and then deagglomerating or grinding the particles using an in-line jet mill. By coupling spray drying with "in-line" jet milling, a single step process is created from two separate unit operations, and an additional collection step is eliminated, which otherwise would be associated with a yield loss and possible aseptic transfer which would be undesirable for pharmaceutical production. The one-step, in-_ 15 line process has further advantages in time and cost of processing. In an optional embodiment, the systems also provide in-line blending of an excipient material with the particles. The jet miliing step beneficially lowers residual moisture and solvent levels in the particles, leading to better stability and handling properties for dry powder 20 pharna ceutical formulalions or other dry powder froms comprising the partitles. As used hertin, the tenn "in-line" refers to process equipment in fluid comniunication arranged and adapted to process the materials in a continuous, sequential manner. That is, the particles being processed flow between and throtigh the individual pieces of equipment, without an intervening collection step. 25 In a preferred embodiment the particles are microparticles. In a preferred method, the microparticles comprise one or more pharmaceutical agents. In one embodiment, the microparticle is formed entirely of a pharmaceutical agent In another embodiment, the microparticle has a core of pharmaceutical agent encapsulated in a shell In yet another embodment, the pharmateutical agent is 30 interspersed within, the shell or matrix. In another embodiment, the pharmaceutical agent is uniformly mixed within the material comprising the shell or matrix. Optionally, the microparticles of any of these embodiments can be blended with one or more excipients. 6 WO 2004/060547 PCT/US2003/037108 As used herein, the terms "comprise," "comprising," "include," and "including" are intended to be open, non-limiting terns, unless the contrary is expressiy indicated. 1. In-Line Methods and Apparatus making Particles The methods include (a) spraying an emulsion, solution, or suspension, which 5 comprises a solvent and a bulk material, through one or more atomizers and into a primaiy drying chamber having a drying gas inlet, a discharge outlet, and a dicing gas flowing therethrough, to form droplets comprising the solvent and the bulk material, wherein, the droplets are dispersed in the drying gas; (b) evaporating, in the primary drying chamber, at least a portion of the solvent into the drying gas to solidify the 10 droplets and form particles dispmed in the drying gas, the particles dispersed in the drying gas being a feedstream; and (c) flowing the particles and at least a portion of the drying gas of the feedstream through jet null to deagglomerate or grind the particles, in a preferred embodiment, step (c) is conducted to deagglomerate at least a, portion of agglomerated particles, if any, while substantially maintaining the size and morphology 35 of the indiyidual particles, Alternatively, step (c) is conducted to grind the particles. In a preferred embodiment, the feedstream of step (b) is directed through a particle concentration means to separate and remove at least a portion of the drying gas from the feedstream. This provides a concentration of solids in the dispersion entering the jet mill that is high enough to permit the jet mill to operate effectively as intended, 20 i.e., to deagglomerate or grind the particles. In another preferred embodiment, which can ne used with or without the particle concentration means, the apparatus includes one or more secondary drying chambers intoposed between, and in fluid communication, with, the discharge outlet of the primary drying chamber and the inlet of the jet mill. These secondary drying chambers 25 provide additional drying of the particles, that is, they provide time and volume for evaporation of a second portion of the solvent into the drying gas. In yet another embodiment, which can be used with or without the particle concentration means and with or without the secondary drying chambers, the apparatus includes a means for introducing another material into the particles and drying-gas 30 flowing batwecn the discharge outlet of the primary drying chamber and the inlet of the jet mill. In one embodiment, this other material could be an excipient, a second pharmaceutical agent, or a combination thereof. For example, a diy powder beta agonist could be introduced into a fead stream from a spray dryer that is pruducing 7 WO 2004/060547 PCT/US2003/037108 microparticles containing a corticosteroid This apparatus can be used, for example, to make a dry powder blend in a single step, i.e., without an intermediate collection step between spray drying and jet milling. FIG- 1 illustrates one example of an in-line system, or apparatus, 10 for making 5 and jet-milling particles. A liquid feed (i.e,, an emulsion, solution, or suspension, which comprises a solvent and a bulk material) and an atomization gas (e.g,, air, nitrogen, etc.) are fed through an atomizer 14. The atomized droplets of solvent and bulk material are formed in the primary drying chamber 12. A drying gas is fed through an optional neater 18 and into a primary drying chamber 12. In the primary drying 10 chamber, the droplets are dispersed in the drying gas, and at least a portion of the solvenl is evaporated into the drying gas to solidify the droplets and form a feed a feedstream of particles dispersed in the drying gas. This feedstream then exits the primary drying chamber 12 through outlet 16 and enters (optional) secondary drying apparatus 20, which includes a coiled tube through which the feedstream flows. Upon 15 exiting the secondary drying apparatus 20, the dispersion enters the cyclone separator 22, which serves to concentrate the particles. A portion of the drying gas is separated from the feedstream and exits the top vent 23 of the cyclone separator 22. The concentrated particles/drying gas then, exits the cyclone separator 22 and flows into a jet mill 24. A grinding gas (e,g., dry nitrogen) also is supplied to the jet mill 24. The jet 20 mill 24 deagglomerates or grinds lie particles, depending, in part, on the operating parameters selected for the jet mill, The jet-milled particles dispersed in drying gas (and grinding gas) then flow from the jet mill 24 to a collection cyclone 26. The jet- entiled particles are collected in collection jar 28 or other suitable apparatus, and the drying and grinding gases are exhausted from the system 10, The exhaust gas from the 25 cyclones 22 and 26 typically is filtered (filters not shown) before release from the system and/or into the atmosphere. FIG. 2 illustrates one example of an in-line system, or apparatus, 40 for making particle blends. In the embodiment shown, particles are made by spray drying, directly blended with an excipient using an in-line excipient feed device, and then the resulting 30 bleod is Jet-miilled using an in-line jet mill, to yield a highly uniform particle blead. The process is like that shown in FIG. 1, except an excipient material (or pharmaceutical material or combination thereof) is added to the particles/drying gas, 8 WO 2004/060547 PCT/US2003/037108 after, or more preferably before, the particles/drying gas flows through cyclone separator 22. The resulting mixture of particles, excipient material, and drying gas then flows into jet mill 24, where the mixture is deagglomerated or ground. The jet-milled paricle/excipient blend dispersed in drying gas then flows from the jet mill 24 to a 5 collection cyclone 26 and collected in collection jar 28. The drying gas and grinding gas are exhausted from system 40, as described above. Preferably, the methods and systems are adapted for making pharmaceutical formulations comprising microperticles, Ths microparticles are made by spray drying, and the jet milling is effective to deagglomerate or grind the microparticles. The jet- 10 milling step can advantageously reduce moisture content and residual solvent levels in the formulation through the addition of dry and solvent free gas directly to the jet mill (e.g., as grinding gas). The jet-milling step also can improve the suspendability and wettabillty of the dry powder formulation (e.g., for better injectability) and give the dry powder formulation improved aerodynamic properties (e.g., for better pulmonary 15 delivery). The use of a of a spray dryer wilh an in-line jet mill, as opposed to a two-step process of a spray drying followed by a separate jet milling process, advantageously improves yield, reduces time, and reduces cost. Spray Drying 20 The particles are formed by a spray drying technique known in the art For example, the particles can be produced using the spray drying methods and devices described, for example, in U.S. Patent No. 5,853,698 to Straub et al, U.S. Patent No. 5,611,344 to Bernstein et al., U.S. Patent No, 6,395,300 to Straub et al., and U.S. Patent No, 6,223,455 to Chickering III, et al. 25 As used herein (in the examples), the symbol "XXX" is used to indicate the term "diameter" for the object being described. As used herein, the term "solvent" refers to the liquid in which the material forming the bulk of the spray dried particle is dissolved, suspended, or emulsified for delivery to the atomizer of a spray dryer and which is evaporated into the drying gas, 30 whether or not the liquid is a solvent or nonsolvent for the material. Other volatilizable components, such as a volatile salt, may be included in the bulk material/liquid, and volatilised into the drying gas. 9 WO 2004/060547 PCT/US2003/037108 In one embodiment, imcropaticles are produced by dissolving a pharmaceutical agent and/or shell material in an appropriate solvent, (and optionally dispensing a solid or liquid active agent, pore forming agent (e,g., a volatile salt), or other additive into the solution containing the pharmaceutical agent and/or shell material) and then spray 5 drying the solution, to from microparticles. As defined herein, the process of "spray drying" a solution containing a pharmaceutical agent and/or shell material refers to a process wherein the solution is atomized, to form a mist and dried by direct contact with carrier gases. Using spray drying equipment available in the art, the solution contxining the pharmaceutical agent and/or shell material-may "be atomized into a drying chamber, 10 dried within the chamber, and then collected via a cyclone at the outlet of the chamber. Representative examples of types of suitable atomization devices include ultrasonic, pleasure feed, air atomizing, and totaling disk- The temperature may be varied defending on the solvent or materials used. The temperature of the infer. and outlet parts can be controlled to produce the desired products. Multiple nozzles (or other 15 atomization devices) can be used to allow for introduction of multiple emulsions, solutions, suspensions, or combinations thereof into the primary drying chamber. The multiple nozzles can be used, for example, to introduce materials that comprise a pharmaceutical agent, an excipient, or combinations thereof, In one embodiment, the multiple nozzles are used to spray the same materil (from each noazle) in order 20 increase process throughput of the material. In another embodiment, the multiple nozzles are used to spray different materials (e.g., different materials from each noazle), for example, in order to create dry powders that are mixtures of different particles, e.g., composed of different materials, The size of fhe particulates of pharmaceutical agent and/or shell material is a 25 function of the nozzle used to spray the solution of the pharmaceutical agent and/or shell material, nozzle pressure, the solution and atomization flaw rates, the pharmaceutical agent amd/or shell material used, the concentration, of the pharmaceutical agent and/or shell material, the type of solvent, the temperature of spraying (both inlet and outlet temperature), and the molecular weight of a shell 30 material such as a polymer or other matrix material. Generally, if a polymer is used the higher the molecular weight, the larger the particle size, assuming the concentration is the same (because an increase in molecular weight generally increases the solution viscosity). Particles having a target diameter between 0.5 um and 500 um can be 10 WO 2004/060547 PCT/US2003/037108 obtained. The morphology of these wicropaticles depends, for-example, on the selection of shell material, concentration, molecular weight of a shell material such as a polymer or other matrix material, spray flow, and drying oonditions. In an optional embodiment, the apparatus further includes one or more 5 secondary drying chambers downstream from the primary drying chamber to provide additional solvent removal. In one embodiment, the secondary drying chamber comprises the drying apparatus described in U.S. Patent No. 6,308,434 and U,S. Patent No. 6,223,455. The secondary drying chamberpreferabry comprises fubing having an inlet in fluid communication with the discharge outlet of the primary drying chamber, to 10 evaporole a second portion of the solvent into the drying gas, wherein the ratio of the cross -sectional area of the primary drying chamber to the cross-sectional area of the tubing is at least 4:3, and wberein the ratio of the length of the tubing to the length of the primary drying chamber is at least 2:1. Particle Concentration Means and Process Control 15 The paiticle concentration means can be essentially auy device suitable for conentrating the particles in the drying gas such that the particles can be effectively jet milled, whether for grinding or deaggiometation. Representative devices for concentrating the particles in the drying gas include cyclone separators, gravity settling chambers (knock-out pots), electrostatic charge precipitators, impingement separators, 20 mecharical centiifugal separators and uniflow cyclones. In a preferred embodiment, the particle concentration means includes at least one cyclone separator as known in the art, to separate and remove at least a portion of the drying gas from said particles, In a typical embodiment, the cyclone separator consists of a vertical cylinder with a conical bottom. The particlc/dfying gas dispersion 25 enters the cyclone through a tangential inlet near the top, entering in a vortical motion. The centrifugal force created, causes the panicles to be thrown toward the wall, and the drying gas folls downward along the wall and then spirals upward through the center when it reaches the bottom, producing a double vortex. The particles fall by gravity to the bottom of the device. One skilled in the art can select the appropriate dimensions of 30 the separator based, for example, on the flow rates of gas and particles, percentage of gas to be separated, system pressures, particle mass and size, etc. For a particular system, successful operation requires balancing of the flows and pressures in the process -equipment, such that jet mill performance is maximized, 11 WO 2004/060547 PCT/US2003/037108 particle blowhack from the jet mill is avoided, and clogging of the cyclone and/or jet mill is avoided. For example, as shown in FIG. 1 and FIG- 2, control of the flow through the system 10 or system 40 can be performed with the use of a control valve 30 downstream from the collection eyelone 26 and/or a control valve 32 downstream from 5 the separator cyclone 22, eithe or both of which can be used to conrol the pressure on the systems. For example, by increasing the backpressure on the system, more drying gas can be separated and expelled through the top vent of the cyclone separator. Altermatively, less drying gas can be directed through the top vent of the cyclone separator by lowering the backpressure on the system. Alternatively, the drying gas 10 exhusted through the cyclone separator can be in part or entirely redirected into the system downstream of the jet mill outlet Optionally, fresh gas can be added into the system downstream of the jet mill outlet. Such redirected or added gases can be used to balance pressures in the process. While a control valve is shown in FIGS-1 and 2, other flow controniug devices 25 known in the art can be used to control the system pressure and/or flow rats of drying gas dischaiged from the particle concentration means or the collection cyclone. For example, the flow controlling devices could comprise a device selected from control valves, fillers, regulatore, orifices, and combinations thereef. In one embodiment, the solids content of the feedstream (particles/drying gas) 20 from the primary and secondary drying chambers is increased by separating aut between about 50 and 100 vol.%, more preferably about 90 and 100 vol,%, of the drying gas, which is expelled through top vent 23. For example, in one embodiment, the flow rate of the particles/drying gas from the apray dryer is52CFM (1500 L/min.) and the flow rate of the particles/drying gas to the jet mill is 0.52 CFM (15 L/nim ). The system 25 components would be sized to maintain the appropriate gas velocity throughout the process. Jet Milling As used herein, the terms "jet nill" and "jet milling" include and refer to the use of any type of fluid energy impact mills, including spiral jet mills, loop jet milk, 30 hammer mills, grinders, crushers, and fludized bed jet mills, with or without internal air classifiers. These mills are known in the art. The jet mill is used to deagglomerate or to grind the particles. As used herein, the term "deagglomerate" refers to the technique for 12 WO 2004/060547 PCT/US2003/037108 albstaotially degglomerating micmparticle agglomerates that have been produced during or subsequent to fomation of the microparticles, by bombarding the feed particles with high velocity air or other gss, typically in a spiral or circular flow. The jet milling process conditions can be selected so that the inucroparticles are substantially 5 deagglomerated while substantially maintaining the size and morphology of the individual microparticles, which can be quantified as providing a volume average size reduction of at least 15% and a number average size reduction of no more than 75%. As used herein, the terms "grind", "ground", or "grinding" refers to particle size reduction by fracture, e.g., conventional milling. That is, the particles and/or 10 agglomerates are induced in size without substantially maintaining the size and morphology of the individual microparticles. The process is characterized by the acceleration of particles in a gas stream to high velocities for impingement on other particles, similarty accelerafed, or impingement on the walls of the mill. A typical spiral jet mill 50 is illustrated in FIG. 3. Particles, with or without 15 drying gas, are fed into feed chute 52. Optional injection gas is fed through one or more ports 56. The particles are forced through injector 54 into chamber 58. The particles enter an extremely rapid vortest in the chamber 58, where they collide with one another until snall enough to become sufficiently entrained in the gas stream, to exit a central discharge port 62 in the jet mill by the gas stream (against centrifugal forces 20 experienced in the vortex). Grinding gas (so-named whether the jet mill is used for grinding or deagglomeration) is fed from port 60 into gas supply ring 61. The grinding gas then is fed into the chamber 58 via a plurality of apertines; only two 63a and 63b are shown. Gnouad or deagglomerated pertictes are discharged from the jet mill 50. The selection of the material forming the bulk of the particles and the 25 temperature of the particles in the jet mill are among the factors that affect deagglomeration and grinding. Therefore, the jet mill optionally can be provided with a temperature control system For example, the control syston may liest the particles, rendering the material less brittle and thus less easily fraetured in the jet mill thereby manimizing unwanted, size reduction. Alternatively, the control system rnay need to 30 cool the particles to below the glass transition or melting temperature of the material, so that deagglomeration is possible. In a preferred embodiment, the particles are aseptically fed to the jet mill, and a suitable gas, preferably dry nitrogen, is used to process the microparticks through the 13 WO 2004/060547 PCT/US2003/037108 mill. Grinding and mjection gas pressures can be adjusted as need, for example, based on the material characteristics. Preferably, these gas pressures are between 0 and 10 bet, more preferably between 2 and E bar. Particle throughput depends on the size and capacity of the jet mill. The jet-milled particles can be collected by filtration or, more 5 preferably, syclone, Jet milling the particles, in addition to providing the desired level of deagglomeration ot grinding, can also lower the residual solvent and moisture levels in the particles or particle blend while in process (i.e., before collection), due to the addition of dry and solvent free gas (e.g., as grinding gas, injection gas. or both) 10 provided to the jet mill. To achieve reduced residual levels, the injection/grinding gas preferably is a low humidity gas, such as dry nitrogen, In one embodiment, the injection/grinding gas is at a temperature less than 100 oC (e.g., less than 75 °C, less than 50°C, less than 25 °C, etc.). Blending 15 In an optional embodiment, the process further includes blending the particles with another material (e.g., an excipient material, a (second) pharmaceutical agent or a combination thereof), which can be in a diy powder form. The blending can be performed before jet milling as an in-line process, after jet mil1ing, ot both before and after jet milling. 20 In a preferred embodiment, the blending is conductsd in a single step process, such as an in-line process, as shown for example in FIG. 2. This process comprises spray drying with in-line blending and in-line jet milling. The excipient material preferably is added to the feedstream before it flows into the jet mill. The excipient material can be introduced into the feedstream using essentially any suitable 25 introduction means known in the ari. Non-Iimiting examples of such introduction means include screw or vibratory feed from a closed hopper, a venhin feed from a vented hopper, via a feedstream from one or more other spray drying units making the excipient particles, or via a feedstream trom one or more jet milling devices, One skilled in the art can readily conned a feed source line using standard techniques and 30 provide the excipient feed material at a sufficient pressure to cause the material to flow into and combine with the drying gas and particles. In another embodiment, the excipient material is blended with the particles post- jet milling, in a batch or continuous process, including an in-line process. The blending .14 WO 2004/060547 PCT/US2003/037108 can be carried out using essentially any technique or device suitable for combining the microparticles with one or more other materials (e.g., excipients), preferably to achieve uniformity of blend. Content uniformity of solid-solid pharmaceutical blends is critical. Jet milling 5 can be conducted on the micropaiticles before blending or as part of a single process (spray drying with in-line blending and in-line jet milling) to enhance content uniformity. Jet-milling advantageously can provide improved wetting and dispersibility upon reconstitution of fee blends, in addition, the resulting micropaiticle formulation can provide improved injectability, passing through the needle of a syringe more easily. 10 Jet milling can provide improved dispersibility of the dry powder, which provides for improved aerodynamic properties for nasal or pulmonary administration. Other Steps in the Process The particles may undergo additional processing steps. Representative examples of such processes include Iyophilization or vacuum drying to further remove 15 residual solvents, temperature conditioning to anneal materials, size classification to recover or remove certain fractions of the particles (i.e., to optimize the size distribution), compression molding to form a tablet or other geometry, and packaging. In one embodiment, oversized (e.g., 20 um or larger preferably 10 um or larger) microparticles are separated from the microparticles of interest Some formulations 20 also may undergo sterilization, such as by gamma irradiation. IL The Partieles The particles made by the processes described herein comprise a bulk material. As used herein, the term "bulk material" includes essentially any material that can be provided in a solution, suspension, or emulsion, and then fed through, an atomizer and 25 dried to form particles. In preferred embodiments, the bulk materiai is a pharmaceutical agent, a "shell material, or a combination of a pharmaceutical agent and a shell material, as described herein. Size and Morphology The particles made by the in-line spray drying and jet mill process can be of any 30 size. As used herein, the term "particle" includes micro-, submicro-, and macro- particles. Generally, the particles ate between about 100 nm and 5 mm in diameter or in the longest dimension. In a preferred embodiment, the particles are microparticles, which are between 1 and 999 microns in diameter or in the longest dimension. As used 15 WO 2004/060547 PCT/US2003/037108 herein, the term "microparticle" includes microspheres and mictocapsules, as well as microparticles, unless otherwise specified. Microparticles may or-may not be spheritical in shaps. Microcapsules are defined as microparticles having an outer shell sunotinding a core of another material, such as a pharmaceutical agent. The core can 5 be gas, liquid, gel, or solid, Microspheres can be solid spheres or can be porous and include a sponge-like or honeycomb structure fonned by pores or yoids in a matrix material or shell. As used herein, the teams "size" or "diameter" in reference to particles refers to the number average particle size, unless otherwise specified. An example of an 10 equation that can be used to describe the number average particlc size is shown below: where n = number of parucles of a given diameter (d). As used herein, the term "vohime average diameter" refers to the volume weighted diameter average. An example of equations that can be used to describe the 15 volume average diameter is shown below: where n — number of particles of a given diameter (d). As used herein, the term "acrodynamic diameter" refets to the equivalent diameter of a sphere with density of 1 g/mL were it to fall under gravity with the same 20 velocity as the particle analysed. Aerodynamic diameters can be determined on the dry powder using an Aerosizer (TSI), which is a time of flight technique, or by cascade impaction or liquid impinger techniques. Particle size analysis can be performed on a Coulter counter, by light microscopy, scaning electron microscopy, transmittance eletron microscopy, laser 25 diffraction methods such as those using a Malvem Mastersizer, light scattering methods or time of flight methods. Where a Coulter method is described, the powder is dispersed in an electrolyte, and the resulting suspension analyzed using a Coulter 16 WO 2004/060547 PCT/US2003/037108 Multisizer II fitted with a 50-um aperture tube, In one embodiment, the jet milling proccess described herein can deagglomerate agglomerated particles, such that the size and morphology of the individual particles is substantially maintained That is, a comparison of the particle size before and after jet 5 milling should show a volume average size reduction of at least 15% and a number average size reduction of no more than 75%. It is believed that the jet milling processes will be most useful in deagglomerating particles having a volume average diameter or aerodynamic average diameter greater than about 2 um. In one embodiment, the particles are micioporticles comprising a 10 pharmaceutical agent tor use in a pharmaceutical formulation. These mieroparticles preferably have a number average size between about 1 and 10 um . In one embodiment, the microparticles have a volume average size between) 2 and 50 um. In another embodiment, the inicroparticles have an aerodynamic diamater between. 1 and 50 um. 15 The pharmaceutical agent containing paitides typically are manufactured to have a size (i.e., diameter) suitable for the intended route of adminisitration. Particle size also can affect RES uptake. For intravascular administration, the particles preferably have a diameter of between 0,5 and 8 um, For subcutaneous or intramuscular administration, the particles preferably have a diameter of between about 20 1 and 100 um. For oral administration for delivery to the gastrointestinal tract and for aplication to other lumens or inucosal surfaces (eg.., rectal, vaginal, buccal, or nasal), the particles preferably have a diameter of between 0,5 um and 5 mm. A preferred size for administration to the pulmonary system is an aerodynamic diameter of between 1 and 5 um, with an actual volume average diameter (or an aerodynamic average 25 diameter) of 5 um or less. In one embodiment, the particles comprise microparticles having voids therein. In one embodiment, the microparticles have a number average size between 1 and 3 um and a volume average size between 3 and 8 um. Pharmaceutical Agents 30 The pharmaceutical agent is a therapeutic, diagnostic, or prophylactic agent. The pharmaceutical agent is sometimes iefened to herein generally as a "drug" or "active agsnt" The phannaceutical agent in the fwal powder may be present in an 17 WO 2004/060547 PCT/US2003/037108 amorphous State, a crystalline state, or a mixture thereof, A wide variety of drugs can be loaded into the micropartrcles, These can be small motecules, proteins or peptides, carbohydrates, aligosaocharides, nucleic acid molecules, or other synthetic or natural agents. Examples of suitable drugs include the 5 classes and species of drugs described in Martindale, the Exira Phormcopoeia, 30th Ed. (The Pharmaceutical Press, London 1993). The drug can be in any suitable form, including various salt forms, free acid forms, free base forms, and hydrates. In one embodiment, the pharmaceutical agent is a contrast agent for diagnostic imaging. For example, the agent could be a gas for ultrasound imaging, as described 10 for example in U.S. Patent No. 5,611,344 to Bernstein et al. Other examples of suitable diagoostic agents useful herain include those agents known in the art for use in positron emission tomography (PET), computer assisted tomography (CAT), single photon emission computerized tomography, x-ray, fluoroscopy, and magnetic resonance imaging (MRI). 15 In other embodiments, the pharmacentical agent is a therapeutic or prophylactic agent Non-limiting examples of these agents include water soluble drugs, such as ceftriaxone, ketoeonsizole, ceftazidime, oxaprpzin, albuterol, valacyclovir, urofollitropin, famciciovir, flutamide, enalapril, mefformin, itraconazole, buspirone, gabspentin, fosinopril, tramadol, acarbose, lorasepau, follitropin, glipizide, omeprazole, 20 fluoxetine, lisinopril, tramsdol, levofloxacin, zafirlukast, interfcion, growth hormone, illterieukin, erythropoietin, granulocyte stimulating factor, ruzatidine, bupropion, perindopril erbumine, adenosine, alendronate, alprostadil, benazeprel, betaxolol, hloomycin sulfate, dexfenfluramine, diltiazom, fentanyl, flecainid, gemeilabine, glatimmer acetate granisetron, lamivudine. mangafodipir trisodium mesalamine, 25 nietoprolol fomarate, metronidazole, mightol, moeripril, monteleukasl, ocuteotide acctate, olopatadine, paricalcitol, somatropin, sumetriptan succinate, tacrine, verapamil, nabumetone, trovafloxacin, dolasetron, zidovudine, froasteride, tobramycin, isradipine, tolcapone, enoxaparin, fluconazote, lansoprazole, terbinafine, pamidronste, didanosine, diclofenac, clsapride, venlafexine, troglitezone, fhivastatin, losartan, imiglucerase, 30 donepezil, olanzapine, valsartan, fexofenadine, calcitonin, or ipratropium bromide. Other examples include hydrophobic drugs such as celecoxib, rofecoxib, paclitaxel, docetaxel, acyclovir, alprazolam, amiodaron, amoxicillm) anagrclide, aripiprazole, bactrim, biaxin, budesonide, bulsulfen, carbamazepine, ceftazidine, 18 WO 2004/060547 PCT/US2003/037108 cefprozil, ciprofloxicin, clarithromycin, clozapine, cyclosporine, diazepam, estiadiol, etodolac, famcictovir, fenofibiate, fexofenadine, gemcitabine, genclovir, itrecronazole, lamotrigine, loratidine, lorazepatn, meloxicam, mesalamine, mitiocyclime, modafinil, nabumetone, nelfinavir mesylate, olanzapine, oxcarbazepine, phenytoin, propofal, 5 ritinavir, risperidone, SN-38, sulfarometuoxazoI, sulfasalazine, tacrolirous, tiagabine, tizamdine, trimethoprim, valium, valsartan, voriconazule, zafiriukast, zileuton, and aiprasidone. In this embodiment, the partieles made by the processes destribed heirein preferably are porous. In One embodiment, the pharmaceutical agent is for pulmonary administration. 10 Non-limiting examples include corticosteroids such as budesonide, fluticasone propionate beclomcthasone diptopionate, mometasone, flumisolide, and triamcicolone acetonide; other steroids such as testosterone, progesterone, and estradiol; leukotriene inhibitots such as zafirlukast and zileuton; antibiotics such as cefprozil, amoxicillin; antifoogals such as ciprefloxscri, and itraconazole; hronchodilators such as stbuterol, 15 formoterol and salmeterol; snoneoplsstics such as pachtaxel and docetaxel; and peptides or proteins such as insulin, calcitonin, leuprolide, granulocyte colony- stimuiating factcr, porathyroid bonrmone-related peptide, and somatostatin Examples of preferred drugs. include aripirazole, tisperidone, albuterol, adapalene, doxazosin mesylatf, mometasone furoate, ursodiol, amphotericin, enalapril 20 maleale, felodipine, nefazodone hydrochloride, valrubicin, albendazole, conjugated estrogens, medtoxyprogesterone acetate, nicandrpine hydrochloride, zolphdem tartrape, amlodjpine besylatate, ethinyl estradinl omeprazole, rubitiecan, amlodipine besylate/ benazepril hydrochloride, etodolac, paroxetine hydrochloride, paclitaxel atovaquone, felodipine, podofilor, paricalcitol, betamethasone dipropionate, fentanyl, pramiperole 25 dihydrochloride, Vitanun D, and related analogues, fmasteride, quetiapine fumarate, alpresiacil, candesartan, cilexetil, fluconazole, ritonavir, busulfan, cartramazepine, flumazenil, nsperidonc, carbemazepine, carbidopa,levodapa, ganciclovir, saquinavir, amprenavn, carboplatin, glyburide, settraline hydrochloride, roferoxib carvedilol, halobetasolproprionate, sildenafil citrate, oelecoxib, chlorthalidone, imiquitnod, 30 simvastatin, citalopran, cipofloxacin, irinolecan hydrochloride, spartloxacin, efavirenz, cisapride monobydrate, lansoprazole, tamsulosin hydrochloride, mofafinil, clarithromycin, letrozole, terbinafine bydrochloride, rosiglitazone maleate, diclofernac sodium, lomefloxacin hydrochloride, tirofiban hydrochloride, telmisartan, diazapam, 19 WO 2004/060547 PCT/US2003/037108 lorafadine, toremifefene citrate, thalidortude, dinoprosione, mefloqume hydrocbloride, trandolspril, docetaxel, initoxantrone hydrocchloride, tretinoin, etodolac, triamcinolone aoetate, estradiol, ursodiol, nelfinavir mesyiate, indinavir, beciomethasone dipropionate, oxaprozin, flutamide, famotidine, nifedipine, prednisone, cefuroxime, lorazepam, 5 digoxin, lovastatin, griseofulvin, naproxen, ibuptofen, isotretimoin, tamoxifen citrate, nimodipine, amiodarone, budestmide, formoterol, flucusone propionates saimeterol, and Shall Material The shell material can be a synthetic material or a natural material. The shell 10 uiareriai can be water soluble or water insoluble. The particles can be fomed of non- biodegradable or biodegradable materials, although biodegradable materials are preferred, particularly for parenteral administration. Examples of types of shell materials include polymers, amino acids, sugars, proteins, carbohydrates, and lipids, Polymeric shell materials can be degradable or non-degradable, crodible or non- 15 erodible, natural or synthetic. Non-erodible polymers may be used for oral administration. In general, synthetic polymers are preferred due to more reproducible synthesis and degradation, Natural polymers also may be used Natural biopolymers that degrade by hydrorysis, such as polyhydroxybutyrate, may be of particular interest. The polymer is selected based on a variety of perfonrmance factors, including the time 20 required for in vivo stabihty, i,e,, the time required for distribution to the site where delivery is desired, and the time desired for delivery. Other salection factors may include shelf life, degradstion rale, mechanical properties, and glass transition temperature of the polymer. Representative synthetic polymers include poly(bydroxy acids) such as 25 poly(lactic acid), poly(glycolic acid), and poly(lactic acid-co-glycolic acid), poly(lactide), poly(glycolide), poly(lactide-co-glycolide), poiyanhydrides, polyorthoester, polyamides polycarbonates polyalkylenes such as polyethylene and polypropylene, polyalkylene giycols such as poly(ethylene glycol), polyajkylene oxides such as poly(ethylcne oxide), polyalkylene terepthalatets such as polyethylene 30 terephthalate), polyvinyl alcohols, polyviayl ethers, palyvinyl esters, polyvinyl balides such as poly(vitiyl chloride), palyvinytpyrrotidone. polysiloxaues, poly(vinyl alcohols), poly( vinyl acete),polystyrene, polyurethanes and co-polymers thereof, derivativized celluloses such as alkyl cellulose, hydroxyalkyl celluloses, cellulose ethers, cullulose 20 WO 2004/060547 PCT/US2003/037108 estas, nitra celluloses, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxy-propyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butycate, cellulose acetate ptathalate, carhoxyethyl cellulose, cellulose triacetate, and cellulose sulphate sodium salt jointly 5 referred in herein as "synthetic celloloses"), polymers of acrylic acid, methaciylic acid or copolymers or derivatives thereof including esters, poly(methyl methacrylste), poly(ethyl methacrylate), poly(butyImethacrylate), poly(isobutyl methocrylate), poly(hexylmethacrylate), poly(isodecyl methacrylats), poty(lauryl methacrylate), poly(phenyl methacrylate), poly (methyl acrylate), poly(isopropyl acrylate), 10 poly(isobutyl acrylate), and poly(octadecyl acrylate) (jointly referred to hercin as "polyacrylic acids"), poly(butyric acid), poly(vileric acid), and poly(lactide-co- caprolactone), copolymers and blends thereof. As used herein, "derivatives"include polymets having substitutions, additions of chemical groups, for example, alkyl, altylene, hydroxylations, oxidations, salt formations, and other modifications routinely 15 made by those skilled in the art. Examples of preferred biodegradable polymers include polymers of hydroxy acids such as lactic acid and glycolic acid, and copolymers with PEG, polyarhydrides, poly(ortho)esters, polyurcthanes, poly(butyric acid), poly(valeric acid), poly(lactide-co- csprolaetone), blends and copolymers thereof. 10 Examples of preferred natural polymers include proteins such as albumin and prulamines, for example, zein, and polysaccharides such as alginate, cellulose and polyhydroxyalkanoates, for exarnple, polyhydrxybutyrate, The in vivo stability of the matrix can be adjusted during the production by using polymenrs such as polylactide-co- glycolide copolynierized with polyethylene glycol (PEG), PEG, if exposed on the 25 external surface, may extend the time these materials circulate, at it is hydrophilic and has been demonstrated to mask RES (reticuloendothehal system) recognition. Examples of preferred non-biodegradable polymers include ethylene vinyl acectate, poly(meth)acrylic acid, polyamides, copolymers and mixtures thereof. Bioadhesive polymers of particular interest for use in targeting of mucosal 30 surfaces incluls polyarihydrides, polyacrylic acid, poly(methyl methacrylates), poly(ethyl methacrylates), poly(butylmethacrylate), poly(isobutyl methacrylate), poly(hexylmethacrylate), poly(isodecyl inethacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), 21 WO 2004/060547 PCT/US2003/037108 poly(isobutyl acrylate), and poly(octadecyl acrylate). Representative amino acids that can be used in the shell include both naturally occurring and non-naturally occurring amino acids. The amino acids can be hydraphobic or hydrophilic and may be D amino acids, L amino acids or racemic 5 mixtures. Amino acids that can be used include glycine, arginine, histidine, threonine, asparagine, aspartic acid, serine, glutamate, proline, cysteme, methionine, valine, leucine, isoleucine, tryptophan, pheaylalanine, tyrosine, lysine, alanine, and giutanine. The amino acid can be used as a bulking agent, or as an anti- crystallization agent for drugs in the amorphous state, or as a crystal growth inhibitor for drags in the crystallins 10 state or as a wetting agent. Hydrophobic amino acids such as leucine, isoleucine, alanine, glucine, "valine, proline, cysteine, inethionine, phenylalanine, tryptophan are more likely to be effective as anticrystallization agents or crystal growth inhibitors, In addition, amino acids can serve to make the shell have a pH dependency that can be used to influence the pharmaceutical properties of the shell such as solubility, rate of 15 dissolution or wetting. The shell material can be the same or different from the excipient material, if present In one embodiment, the excipient can comprise the same classes or types of material used to form the shell. In another embodiment, the excipient comprises one or more materials different from the shell material In this latter embodiment, the 20 excipient can be a surfactant, wetting agent, salt, bulking agent, etc. In one embodiment, the formulation comprises (i) microparticles that have a core of a drug and a shell comprising a sugar or amino acid, blended with (ii) another sugar or amino acid that functions as a bulking or tonicity agent Excipients 25 For particles to be used in pharmaceutical applications, the term "excipient" refers to any non-active ingredient of the formulation intended to facilitate delivery and administration by the intended route. For example, the excipient can comprise amino acids, sugars or other carbohydrates, starches, surfactants, proteins, Iipids, or combinations thereof. The excipient may enhance handling, stability, aerodynamic 30 properties and dispersibility of the active agent In preferred embodiments, the excipient is a dry powder (e.g., in the form of microparticles), which is blended with drug microparticles. Preferably, the-excipient microparticles are larger in size than the pharmaceutical micro-particles. In one 22 WO 2004/060547 PCT/US2003/037108 embodiment, the excipient microparticles have a volume average size between about 10 and 1000 um. preferably between 20 and 200 um, more preferably between 40 and 100 Representative amino acids that can be used in the drug matrices include both 5 naturally occurring and non-naturally occurring amino acids. The amino acids can be hyckophobic or hydroplulic and may be D amino acids, L amino acids or racemic mixorres. Non-limiting examples of amino acids that can be used include glycine, argmme, histidine, threanine, asparagus aspartic acid, serine, glulamate, proline, cysteine methionine, valine, leucine, isoleucine, tryptophan, phenylalanine, tyrosine, 10 lysine, elanine, glutamine. The ammo acid can be used as a bulking agent, or as a crystal growth inhibitor for drugs in the crystalline state or as a wching agent Hydrophobic amino acids such as leucine, isoleucine, alanine, glucine, valine, proline, cysteine, methionine, pnenylalamine, tryptophan are more likely to be effective as crystal growth inhibitors, In addition, amino acids can serve to make the matrix have a 15 pH dependency that can be used to influence the pharmaceutical properties of the matrix such as solubility, rate of dissolution, or-wetting. Examples of excipients include pharmaceutically acceptable carriers and bulking agents, including sugars such as lactose, mannitol, trehalose, xylitol, sorbitol, dextran, sucrose, and fructose. Other suitable excipients include aurface active agents. 20 dispersants, osniotic agents, binders, disintegrants, glidants, dilucuts, color agents, flavoring agent, sweeteners, and jubric-ants. Exaropies include soddium desoxycholate; sodium dodecylsulfate; polyoxyethylcne sorbitan fatty acid esters, e.g., polyoxyethylene 20 soibitan monolaurate (TWEEN™ 20), polyoxyethylene 4 sorbitan monolaurate (TWEEN™ 21), polyoxyethylene 20 sorbitan monopalmitate (TWEEN™ 40), 25 polyoxyethylene 20 sorbitati monooleate (TWEEN™ 80); polyoxyethylene alkyl ethers, e.g., polyoxyelhylene 4 lauryl ether (BRU™ 30), polyoxyethylene 23 lauryl ether (BRU™ 35), polyoxyethylenc 10 olyl ether (BRUTM 97); and polyoxyethylene glycol esters, e.g., poloxyethylene 8 stearate (MYRJ™ 45), poloxyethylene 40 steasate (MYRJ™ 52), Spans, Tyloxapol or mixtures thereof. 30 Examples of binders include starch, gelatin, sugars, gums, polyethylene ghycol, ethylcellulose, waxes and polyvinylpyrrolidone. Examples of disintegrants (including super disintegrants) include starch, clay, celluloses, croscarmnelose, crospovidonc and sodium starch glyoolate. Examples of glidants include colloidal silicon dioxide and 23 WO 2004/060547 PCT/US2003/037108 talc. Examples of diluente include dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch and powdered sugar. Examples of lubricants include tale, magnesium stearate, calcium steatate, steatic acid, hydiogenated vegetable oils, and polyethylene glycol. 5 The amounts of excipient for a particular formulation depend on a variety of factors and can be selected by one skilled in the art Examples of these factors include the choice of exicipient, the type and amount of drug, the micropartficle size and morphology, and the desired properties and route of administration of the final formulation. 10 In one embodiment for injectable microparticles, a coimbination of mannitol and TWEEN™ 80 is tended with polymeric microspheres. In one case, the mannifol is provided at between 50 and 200 % w/w, preferably 90 and 130 % w/w, microparticles, while the TWEENTM 80 is provided at between 0.1 and 10 % w/w, preferably 2,0 and 5,1 % w/w microparticles. In another case the mannitol is provided with a volume 15 average particle size between 10 and 500 um. In another emboment, the exripient comprises lactose for an inhaled dosage form. In yet another embodiment, the excipient comprises binders, disintegrants, glidants, diluent color agents, flavoring agents, sweeteners, and lubricants for a solid 20 oral dosage form such as a capsule, a tablet, or a wafer, Forparticles to be used in non-pharmaceutical applications, the term "excipient" refers to essentially any material that can be blended with the particles for any purpose. III, use of the Particles Particles tnade using the processes described herecin can be used in a wide 25 vsriety of spplications and industries, including albcasives, agricultural products, biochemical product chemicals, cosmetics, dyes, foods, metals, pigments, and pharmacenticals. For some applications, the particles preferably are microparticles. In a preferred embodiment, the particles are microrparticles for use in a pharmacentical formulation, which can be administered to a human or animal in need 30 thereof, for the delivery of a therapeutic, diagnostic, or prophylactic agent in an effective amount. The formulations can be administered in dry form or dispersed in a physiological solution for injection or oral administration. The dry form can be acrosolized and inhaled for pulmonary administration. The toute of administration 24 WO 2004/060547 PCT/US2003/037108 depends on the pharmaceutical agent being delivered. In one embodiment, microparticles or blends of microparticles/excipient are jet milled to deagglomerate the particles and then further processed, using known techniques, info a solid oral dosage from Examples of such solid oral dosage forms 5 include powder-filled capsules. lablets, and wafers, The jel-milling advantageonsly can provide improved wetting and diapersibility upon oral dosing as a solid oral dosage from formed from these microparticles or microparticle/excipient blends. The invention can further be understood with refereunce to the following non- limiting examples. 10 Example l: Spray Drying of PLGA Microspheres Without Milling (Comparative Example) This example describes a process for making PLGA microspberes, The micropheres were made in a batch spray drying process. A polymer emulsion was 15 prepared, composed of droplets of an aqueous phase suspended in a continuous polymer/organic solvent phase. The polymer was a commercially obtained poly(lactide-co-glycolide) (PLGA) (50:50). The organic solvent was methytene chloride. The resulting emulsion was spray dried on a custom spray dryer with a dual drying chamber set-up. The process conditions resulted in a theoretical solids to drying 20 gas mass flow ratio of 4,77 g solids/min.; 1.6 kg nitrogen/min, The outlet temperature of the primary drying chamber was maintained at 12 oC. The discarga of the primary drying chsmber was connected to a custorn secondary drying chamber comprising 100 feet of 1.5" XXX coiled tubing, enveloped by a water-cooled jacket The discharge of the secondary drying, chamber was connected to a cyclone collector having a, 1" XXX inlet, a 25 1 "XXX exthaust outler, and a 1.5" XXX dust outler. Three replicate barches were genirated Particte size "was measured using a Coulter Multisizer II with a 50 um aprture. Table 1 presents the averages size results for the three batches. 30 25 WO 2004/060547 PCT/US2003/037108 Example 2: PLGA Micr oparticles Formed Using an In-Line Spray Drying / Jet Milling Process PLGA microspheres were produced using a batch spray drying process with an in-line jet mill. A polymer emulsion was prepared, composed of droplets of an aqueous 5 phase suspended in a continuous polymer/organic solvent phase. The polymer was a commercially obtained poly(lactide-co-glycolide) (PLGA) (50:50). The organic solvent was methylene chloride. The resulting emulsion was spray dried on a custom spray dryer with a dual drying chamber set-up. The process conditions resulted in a theoretical solids to drying gas mass flow ratio of 4.77 g solids/min : 1.6 kg 10 nitrogen/min The outler temperature of the primacy drying chamber was maintained at 12 oC The discharge of the primary drying chamber was connected to a secondary drying chamber comprising 100 feel of 1.5" XXX coiled tubing, enveloped by a water- cooled jacket. The discharge of the secondary drying chamber was connected to a concentrating cyclone having a 1" XXX inlet, a 1" XXX exhaust outlet, and a 1.5" XXX dust 15 outlet. A 0 2 um filter was attached to each of the concentrating cyclone exhausts. A jet mill (Hosokawa 50AS) was connected to the concentrating cyclone dust outlet using a 1 S\ 2" short reducer. Dry nitrogen was supplied to the jet mill for grinding and injection gas. the jet mill was operated at P1 = 3 bar and Pg = 2.9 bar. A cyclone collector, having a 3/8" XXX inlet, a 3/4" XXX exhaust outlet, and a 3/4" XXX dust outlet, was 20 connected to, the discharge of the jet mill to collect the microspheres. A 0,2 um filter was attached to the jet mill cyclone exhaust. This experiment was conducted in triplicate. An average product yield of 56.5±4.2% was obtained. Particle size was measured using the same method as in Example 1, and the average results for the three batches are shown in "Table 2. Table 3 provides a comparison of the average size results of the unmilled and in-line milled microspheres from Examples 1 and 2. WO 2004/060547 PCT/US2003/037108 This demonstrates that in-line jet milling was effective in deagglomeration. Example3: Batch Processing of Celecoxib Microspheres (Comparative Example) 5 Celecaxib (CXB) miciospheres were produced using a batch spray drying process. A solution containing CXB in 800 mL of methanol-water (65:35) was spray dried on a custom spray dryer with a single drying chamber. The process conditions resulted in a theoretical solids to drying gas mass flow ratio of 0.24 g solids/min : 1.7 kg nitrogen/min. The outlet temperature of the drying chamber was set at 20 oC The 10 discharge of the drying chamber was connected to a cyclone collector having a 1"XXX inlet, a 1 " XXX exhaust outlet, and a 1.5" XXX dust outlet Duplicate batches were generated. Yield was calculated as the mass of dry product divided by the dry mass of non-volatile masterials in the feed stock. Geometric particle size (volume mean) was measured using an Aerosizer particle sizer set at both 15 high shear and zero shear. Table 4 presents the yield and size insults for the two batches. The powder from Experiment No, 3.1 was fed manually into a Fluid Energy 20 Aljet Jet-O-Mizer jet mill at a feed rate of about 1 g/min. Dry nitrogen gas was used to drive the jet mill The operating parameters were 4 bar grinding gas pressure and 8 bar injection gas pressure. A cyclone collector, having a 3/8" x 3/4" rectangular inlet, a 3/4" XXX exhaust outlet, and a 1/2" XXX dust outlet, was connected to the discharge of the jet mill to collect the microspheres. Yield and particle size were measured using the same 25 methods as described above within the Example. Table 5 compares the results of the pre-milled material (Experiment No. 3.1) to the results of the batch jet milled material (Experiment No. 3,3). 27 WO 2004/060547 PCT/US2003/037108 The data shows that jet milling reduced the particle size of the CXB powder. The final yield of the batch process can be calculated by multiplying the yield for 5 experiment 3.1 times the yield from experiment 3.2. This calculates to a final process yield of 52% for the batch milled product. Example 4: Celecoxib Microspberes Formed Usiug an In-Line Process CXB microspheres were produced using a spray drying process with an in-line 10 jet mill. A solution containing CXB in 800 mL of methanol-weter (65:35) was spray dried on a custom spray dryer "with a single drying chamber. The process conditions resulted in 8 theoretical solids to drying gas mass flow iatio of 0,24 g solids/min.: 1.7 kg nitrogen/min. The Outlet temperature of the drying chamber was set at 20 oC. The discharge of the drying chamber was connected to a concentrating cyclone harving a 1" 15 XXX intet, a 1" XXX exhaust outlet, and a 1,5" XXX dust outlet A jet mill (Fluid Energy Aljet Jet-O-Mizer) was conneccted directly to the concentrating cyclone dust outlet Dry nitrogen was supplied to the jet mill for grinding and injection gas. The jet mill was operated at Pi = 8 bar and Pg = 4 bar. This experiment was carned out in duplicate, with difienart collection cyclones used in each experiment A cyclone collector, having 20 a 3/8" x 3/4" rectangular inlet, a 3/4" XXX exhaust outlet, and a 1/2" XXX dust outlet, was connected to the discharge of the jet mill to collect the micfospheres for Experiment No. 4.1. A cyclone collector, having a XXX inlet, a 3/4" XXX exhaust outlet, and a 3/4" XXX dust outlet, was connected to the discharge of the jet mill to collect the microspheres for Experiment No. 42. The smail difference in yield between the two collection 25 cyclones used in Experiments No. 4.1 and No. 4.2 was not considered to be significant. Yield and particle size were measured using the some methods as in Example 3, Table 6 presents the average results for the duplicate batches. 28 WO 2004/060547 PCT/US2003/037108 Table 7 provides a comparison, of the average size and yield results of the unmilled, natch milled, and in-line milled CXB microspheres from Examples 3 and 4. 5 In-line jet milling was as effective as batch jet milling in reducing particle size. The in-line process resulted in a higher product yield (64%) than the combination of the batch processes (52%). Example5: Batch Processing of Paclitaxel Mirospheres (Comparative Example) 10 Paclitaxel (PXL) microspheres were produced using a batch spray drying process. A solution containing PXL in 800 mL of etbanol-water (80:20) was spray dried on a custom spray dryer with a single drying chamber. The process conditions resulted in a theoretical solids to drying gas mass flow ratio of 0.83 g solids/min : 2.0 kg nitrogen/min. The outlet temperature of the drying chamber was set at 57 oC, The 15 discharge of the drying chamber was connected to a cyclone collector haying a 1" XXX inlet, a 1" XXX exhaust outlet, and a 1-5" XXX dust outlet. One batch was geuerated Yield was calculated as the mass of dry product divided by the dry mass of non-volatile materials in the feed stock. Geometric particle size (volume mean) was measured using a Mastersizer particle size analyzer set at 20 maximum pressure. Table 8 presents the yield and size results. The powder from Experiment No. 5.1 was fed manually into a Fluid Energy Aljet Jet-O-Mizer jet mill at a feed rate of about 1 g/min. Dry nitrogen gas was used to 25 drive the jet mill. The operating parameters were 4 bar grinding gas pressure and 8 bar injection gas pressure. A cyclone collector, having a 3/8" XXX inlet, a 3/4" XXX exhaust outlet, and a 3/4" XXX dust outlet, was connected to the discharge of the jet mill to collect the mitrospheres. Yield and particle size were measured using the same methods as described above within the Example. Table 9 compares the results of the pre-milled 29 WO 2004/060547 PCT/US2003/037108 material (Experimeat No. 5.1) to the results of the batch milled material (Experiment No. 5.2). 5 The data shows that, in this case, batch jet milling did not significantly change the particle size of the PXL powder. The final yield of the batch process can be calculated by multiplying the yield for Experiment No. 5,1 times the yield from Experiment No. 5.2, This calculates to a final process yield of 49% for the batch milled product. 10 Example 6: Paclitaxel Microspheres Formed Using an In-Line Process PXL microspheres were produced using a spray drying process with an in-line jet mill. A solution containing PXL in 800 mL of ethanol-water (80:20) was spray dried on a custom spray (dryer with a single drying chamber. The process conditions 15 resulted in a theoretical solids to diying gas mass flow ratio of 0,83 g solids/min; 2.0 kg nitrogen/min. The outlet temperature of the drying chamber was set at 57 oC. The discharge of the diying chamber was connected to a concentrating cyclone having a I" XXX inlet, a 1" XXX exhaust outlet, and a 1.5" XXX dust outlet. A jet mill (Fluid Energy Aljet Jet-O-Mizer) was connected directty to the concentrating cyclone dust outlet Dry 20 nitrogen was supplied to the jet mill for grinding and injection gas. The jet mill was operated at P; = 8 bar and Pg = 4 bar. A cyclone collector, having a 3/8" XXX inlet, a 3/4" XXX exhaust outlet, and a 3/4" XXX dust outlet, was connected to the discharge of the jet mill to collct the microspheres for Experiment No. 5.1. Yield and particle size were measured using the same methods as in Example 5. Table 10 presents the results. Table 11 provides a conipari&on of the average siae and yield results of the unmiUed, batch imilled, and in-line milled PXL raicrospheres from Examples 5 and 6. 30 WO 2004/060547 PCT/US2003/037108 In-line-jet milling was more effective than batch jet milling in reducing particle size. The in-line process resulted in a higher product yield (66%) than the combination 5 of the batch processes (45%). Example 7: PLGA Micropartictes formed, Blended with Mannitol/Tween 80, And Jet Milled Using an In-Line Process PLGA microspheres were produced using a single in-line process involving 10 spray drying, blending with mannitol/Tween 80 powder, and jet-milling using the Hosokawa 50AS jet-mill. A polymer emulsion was prepared, composed of droplets of an aqueous phase suspended in a continuous polymer/oranic solvent phase. The polymer was a commercially obtained poly(lactide-co-glycolide) (PLGA)(50:50). The organic solvent was methylene chloride. The resulting eniulsion was spray dried on a 15 custom spray dryer with a dual drying chamber set-up, The mannitol/Tween 80 powder was injected at the discharge of the secondary drying chamber (which is upstream from the concentrating cyclone having a I" XXX inlet, a 1" XXX exhaust outlet, and a 1.5" XXX dust outlet) using a nitrogen feed. The dust outlet of the concentrating cyclone was connected to the inlet of the jet-mill. Another cyclone collector, baying a 1" XXX inlet, a 20 1" XXX exhaust outlet, and a 1.5" XXX dust outlet, was connected to the discharga of the jet- mill to collect the product. The experiment was conducted in duplicate. The particle size of the product obtained from this experiment is given in Table 12. Three samples from Experiment No. 7.1 were reconstituted with 5 ml of RO/DI water, which dissolved the mannitol/Tween 80 powder The microsphere mass for each vial 31 WO 2004/060547 PCT/US2003/037108 was determined by filtering the reconstituted suspension and collecting the undissoived microspheres on the filter. The mess of mamitol/Tween 80 was determined by lyophilizing the filtered solution. The results are given in Table 13. The relative standard deviation (R.S.D) values horn the Table 13 indicate that it was possible to achieve a uniform blend through an in-line process involving.spray drying, blending, and jet milling. Publications cited herein and the meterials for which they are cited are 10 specifically incorporated by reference. Modifications and variations of the methods and devices described herein will be obvious to those skilled in the art from the foregoing detailed description. Such modifications and variations are intended to come within the scope of the appended caims. 32 14-03-2005 US0337108 PCT/US03/037108 We claim: 1. A method for making particles comprising: (a) spraying an emulsion, solution, or suspension, which comprises a solvent and a bulk material, through at least one atomizer and into a primary drying chamber having a drying gas inlet, a discharge outlet, and a drying gas -flowing therethrough, to form droplets comprising the solvent and the bulk material, wherein the droplets are dispersed in the drying gas; (b) evaporating, in the primary drying chamber, at least a portion of the solvent into the drying gas to solidify the droplets and form particles dispersed in the drying gas, the particles dispersed in the drying gas being a feedstream; and (c) flowing the feedstream through an in-line jet mill to deagglomerate or grind the particles. 2. The method of claim 1, wherein before step (c), the feedstream of step (b) is directed through a particle concentration means to separate and remove at least a portion of the drying gas from the feedstream. 3. The method of daim 2, wherein the particle concenrration means comprises a cycl one separator, 4. The method of claim 2, wherein the particle concentration means comprises one or more devices selected from gravity settling chambers, electrostatic charge pretipitators, impingement separators, mechanical centrifugal separators, and uniflow cycloues. 5. The method of any of claims 2 to 4, wherein between about 50 and 100 vol% of the drying gas is separated from the feedstream. 6. The method of claim 1, wherein, before step (c), the feedsiream of step (b) is directed throtigh at least one secondary drying chamber in fluid communication with the discbarge outlet of the primary drying chamber to evaporate a second portion of the solvent into the drying gas. 33 AO1284295.l AMENDED SHEET WO 2004/060547 PCT/US2003/037108 7. The method of claim 6, wherein the at least one secondary drying chamber comprises tubing having an inlet an fluid cammlaucation with the discharge outlet of the primary drying chamber, wherein the ratio of the cross-sectional area of the primary drying chamber to the cross-sectional area of the tubing is at least 4:3, and wherein the ratio of the length of the tubing to the length of the pritnary drying chamber is at least 2:1. 8. The method of any of claims 1 to 7, wherein step (c) is conducted to deagglomerate at least a portion of agglomerated particles, if any, while, substantially maintaining the size and morphology of the individual particles. 9. The method of any of claims 1 to 7, wherein step (c) is conducted to grind the particles. 10. The method of any of claims 1 to 9, wherein the bulk material comprises a phannacentical agent. 11. The method of claim 10, wherein the bulk material further comprises a shell material. 12. The method of claim 11, wherein the shell material is selected from polymers, lipids, sugars, carbotydrates, proteins, peptides, amino acids, and combinations thereof. 13. The method of any of claims 1 to 12, wherein the particles are microparticles. 14. The method of claim 13, wherein the mioroparticles comprise microspheres having voids or pores therein. 15. The method of any of claims 1 to 14, wherein the bulk material comprison a therapeutic or prophylactic agent 16. The method of claim 15, wherein the therapeutic or prophylactic agent is hydrophobic and the particles comprise microspheres having voids or pores therein. 17. The method of any of claims 1 to 16, further comprising adding to the feedstream an excipient material, aphannacenrtical agents or both. 34 14 03-2005 US0337108 PCT/US03/037108 25. A method tor making a dry powder blend comprising: (a) spraying an emulsion, solution, or suspension, which comprises a solvent and a bulk, material, through an atomizer and into a primary drying chamber having a drying gas inlet, a discharge outlet, and a drying gas flowing therethrongh, to form droplets comprising the solvent and the bulk material, wherein the droplets arc dispersed in the drying gas; (b) evaporating, in the primary drying chamber, at least a portion of the sulvent into the drying gas to solidify the droplets and form particles dispersed in the drying gas, the particles dispersed in the drying gas being a feedstream; (c) adding a dry powder material to the feedstream to form a combined feedstream; and (d) flowing the combined feedstream through an in-line jet mill to deagglomerate or grind the particles and dry powder material of the combined fcedstrcam. 26. The method of claim 25, wherein the feedstream or the combined feedstream is direcred through a particle concenrration means to separafe and remove at least a portion, of the drying gas from the feedstrearn or the combined feedstream, respectively. 27. The metaod of claim 25 or 26, wherein the particles are micro particles comprising a pharmaceutical agent and the dry powder material comprises an excipient material, a second pharmaceutical agent, or a combination thereof. 28. The incthud of claim 25 or 26, wherein the particles are microparticles comprising, a pharmaceutical agent and the dry powder material is in the form of microparticles having a size that is largez than the-size of the microparticles comaprising a pharmaceutical agent, 29. The method of any of claims 25 to 28, wherein step (d) is couducled to deagglomerate at least a puilion of aggluneraled parucles, if any, while substantially maintaining the size and morphology of the individual particles. AO1284295.l AMENDED SHEET 14-03-2005 US0337108 PCT/US03/037108 30. An apparalus for making particles comprising: at least one atomizer for spraying an emulsion, solution, or suspension, which comprises a solvent and a bulk material to form droplets of the solveot and the bulk maicrial; a primary drying chamber having a drying gas inlet and a discharge outlet, the atomizer being located in the primary drying chamber which provides for evaporation of at least a portion of the solvent into the drying gas to solidify the droplets and form particles dispersed in the drying gas; and an in-line jet mill having an inlet to fluid commonication with the disoharge outlet primary drying chamber, the jet mill being operable to receive the particles dispersed in at least a portion, of the drying gas and grind or deagglomerate the particles. 31, The apparatus of claim 30, further comprising at least one secondary drying chamber interposed between, and in fluid communication with, the discharge outlet of the primary drying chamber and the intel of the jet mill, wherein the at least out secoudary during chamber provides for evaporation of a second portion of the solvent into the drying 32. The apparatus of claim 31, wherein the at least one secondary drying chamber comprises tubing having an iulet in fluid communication with the dischaige outlet of the primry drying chamher, wherein the ratio of the cross-sectional area of the primary drying chamber to the cross-sectional area of the tubing is at least d-3, and wherein the ratio of the lengh of the tubing to the length of the primary drying chamber is at least 2; 1. 33. The apparatus of any of claims 30 to 32,. further comprising a particle concentration means to separate and remove at least a portion of the drying gas from the particles. 34. The apparatus of claim 33, wherein the particle concentration means comprises one or more devices selected from cyclock; separatous, gravity settling chambers, electrostatic charge precipitators, impingement separators, mechanical centrifugal separanors, and uniflow cycloncs. AO1284295.l AMENDED SHEET WO 2004/060547 PCT/US2003/037108 35. The apparatus of claim 34, further comprising a flow controlling device to control the flaw rate of drying gas discharged from the particle concentration means. 36. The apparatus of claim 30, futher comprising a coliection cyclone to separate the drying gas from the deagglomerated or ground particles which are discharged from the jet mill. 37. The apparatus of claim 36, further comprising a flow controlling device to control the flow rate of the drying gas discharged from the collection cyclone. 38, The apparatus of claim 35 or 37, wherein the flow controlling device comprises a device selected from control valves, filters, regulators, orificest and combinations thereof. 39. The apparatus of claim 30, further comprising a means for introducing an excipient material into the particles and drying gas flowing between the discharge outlet of the primary drying chamber and the inlet of the jet mill. 40. The apparatus of claim 30, comprising a plurality of atomizers disposed in the primary drying chamber. 41. A pharrnaceutical compusition comprising particles made by the method of any of claims 1 to 24. 42. A pharmaceutical composition comprising a dry powder blend made by the method of any of claims 25 to 29. 38 metheds and appuratur are privided for making particles comparsing (1) spraying an emulstion solution or sos- pension, which comprise a solvent and a bult inulcnal (e.g., a phannaceuiletal agent). thought all atulpizer(14) and into a primary Urving chamber (12) having a drying gas following therthrough, to from droplets comprising the solvent and bulk matchal dispersed in the drying gas (b) eraporning, in the primary draying chamber (12), an loast a portion of the solvem into the drying gas to solidify the droplets and rorm paricles dispersed in draying gas and flowing the partiles and of least a portion or the drying gas though a jet mill (24) to deageglomerate or grind the parthcles. By coupling spray drying with "in-line" jet milling, a single step process is ereaied from two separate unit openations. and an additional colletion step is advanlagcosty climtred. The one-step, in-line process has further advanges in utsc and cost of proccessing. |
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| Patent Number | 217417 | ||||||||||||||||||||||||
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| Indian Patent Application Number | 01086/KOLNP/2005 | ||||||||||||||||||||||||
| PG Journal Number | 13/2008 | ||||||||||||||||||||||||
| Publication Date | 28-Mar-2008 | ||||||||||||||||||||||||
| Grant Date | 26-Mar-2008 | ||||||||||||||||||||||||
| Date of Filing | 07-Jun-2005 | ||||||||||||||||||||||||
| Name of Patentee | ACUSPHERE, INC. | ||||||||||||||||||||||||
| Applicant Address | 500 ARSENAL STREET, WATERTOWN, MA 02472, U.S.A | ||||||||||||||||||||||||
Inventors:
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| PCT International Classification Number | B01J 2/04 | ||||||||||||||||||||||||
| PCT International Application Number | PCT/US2003/037108 | ||||||||||||||||||||||||
| PCT International Filing date | 2003-11-20 | ||||||||||||||||||||||||
PCT Conventions:
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